KR20040091099A - Immediate release pharmaceutical granule compositions and a continuous process for making them - Google Patents

Abstract

(i) at least one drug classifiable to Class II or IV of the Biopharmaceutical Classification System, wherein the drug constitutes at least about 0.5% to about 20% by weight of the composition. (ii) a combination of microcrystalline cellulose and a swellable polymer, maltodextrin, cyclodextrin and derivatives thereof, wherein the weight ratio of swellable polymer to microcrystalline cellulose is greater than about 2: 100 and up to about 30: 100 A first excipient selected from the group consisting of at least one dextrin-containing compound, and a mixture of said dextrin-containing compound and said combination, and (iii) a non-aqueous wetting compound or a meltable compound, the solid fraction and optionally a liquid An immediate release pharmaceutical granule composition further comprising a wet amount of a second excipient comprising a fraction.

Description

Rapid release pharmaceutical granule composition and its continuous preparation method TECHNICAL FIELD [0001] IMMEDIATE RELEASE PHARMACEUTICAL GRANULE COMPOSITIONS AND A CONTINUOUS PROCESS FOR MAKING THEM

In order to understand the limitations that can be applied to formulations of drugs with low solubility in water and at the same time the kind of pharmaceutical solid formulations to which the invention belongs, some general considerations regarding drug formulations are provided herein.

Tablets and capsules are generally inadequate for the administration of high doses of biologically active ingredients, as individual large dosage forms are difficult to swallow or require the administration of several tablets or capsules at a time, thereby impairing patient compliance. Do.

Hard gelatin capsules are known in the usual pharmaceutical dosage forms. Since starting to industrially produce drug compositions ranging from 5 (corresponding to 0.13 ml volume) to 000 (corresponding to 1.36 ml volume), the size of the hard gelatin capsules has been standard. Thus, depending on the bulk density of the formulation, when a large amount of ingredient is required for each dosage unit, it may be necessary to use a large size capsule that is too large to be swallowed, or, more preferably, a capsule of size 000 is too small The amount may not be acceptable. Pellets and granules are filled into hard gelatin capsules and have been used as conventional or sustained release dosage forms, but the latter is difficult to prepare.

Therefore, the concept of tableting of coated active ingredient particles is a key issue. Benefits resulting from microencapsulating materials protected from external influences and their inverse, such as increased stability, reduced undesirable reactions or irritation with other components in the mixture, and the ability to mask unpleasant tastes and odors, etc. Attempts have been made to prepare tablets comprising microcapsules. However, the compaction of coated beads or pellets for preparing tablets faces a number of difficulties and problems. As is known in the pharmaceutical industry, beads or pellets are very distinct from granules. Beads may be defined as small, free-flowing, spherical or near-spherical granules prepared by pelleting, ie, agglomeration of fine powders or granules of drugs and excipients using suitable processing equipment. In contrast to the granulation process, the preparation of beads by pelletization increases the average size and narrows the size range distribution.

Another difficult problem is the formulation of drugs with low or very low solubility in water in solid dosage forms for immediate release. The solution to solve this problem is hardly disclosed in the prior art. For example, U.S. Patent Publication No. 2001/0048946 discloses a solid dosage form of a pharmaceutical formulation with very low solubility in water, i.e., a solid or crystalline drug such as Glita having a solubility in water of 10 to 33 μg / ml at 25 ° C. Provide zone. More particularly, this document discloses pharmaceutical compositions in the form of solid particulate dispersions of the pharmaceutical formulations dispersed throughout a matrix of water-soluble polymers such as polyvinylpyrrolidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose. do. In one preferred embodiment, the granular pharmaceutical formulation is dispersed in the water soluble polymer in a weight ratio of about 10% to about 90% active ingredient relative to about 90% to about 10% polymer. Other conventional excipients may be added, such as glycerin, propylene glycol, Tween, stearate and the like.

US Patent Publication No. 2001/0044409 discloses (a) combining a drug with a carrier, (b) dissolving a surfactant and a plasticizer / solubilizer in water, (c) a fluidized bed of a surfactant-plasticizer / solubilizer solution Spraying onto the drug / carrier mixture in the granulator, (d) extruding the obtained granule through a twin screw extruder having at least one heating zone, and (e) grinding the extrudate into a powder mass of solid drug dispersion ( Disclosed is a method for preparing a drug having low solubility in water in a solid dispersion comprising the steps of milling). Within the scope of this method, the carrier may be selected from the group consisting of polyvinylpyrrolidone, high molecular weight polyethylene glycols, urea, citric acid, vinyl acetate copolymers, acrylic polymers, succinic acids, sugars and mixtures thereof; The plasticizer / solubilizer may be selected from the group consisting of low molecular weight polyethylene glycol, propylene glycol, glycerin, triacetin, triethyl citrate, sugar alcohols and mixtures thereof, the surfactant being twin, span , Pluronics, polyoxyethylene sorbitol esters, monodiglycerides, polyoxyethylene acids, polyoxyethylene alcohols and mixtures thereof. This method has the drawback that as it provides a heating zone in the twin screw extruder, the result is to adjust and monitor the temperature profile of the extruder.

However, none of these methods appear to be successful in formulating solid dosage forms of drugs with very low solubility in water, i.e., less than 10 μg / ml, preferably less than 5 μg / ml. This problem is also applicable to a number of drugs, including those belonging to the diaminopyrimidine class as described in US Pat. No. 6,211,185.

US Pat. No. 3,639,637 discloses (by weight) 70-95% water dispersible gelling microcrystalline cellulose and 5-30% finely divided diethylstilbestrol (compound substantially water insoluble), and optionally a composition. An estrogen composition for preparing a stable aqueous suspension that can be sprayed on animal feed further comprising a hydrocolloid selected from the group consisting of sodium carboxy-methylcellulose, methylcellulose and hydroxyethylcellulose, which is no more than 1/3 It starts. The latter two cellulose compounds, ie EP-A-403,383, are known to contribute to an extended linear drug release rate.

EP-A-352,190 discloses solid pharmaceutical units having an active ingredient of delayed solubility, ie allowing the retention of the active ingredient and avoiding complete and rapid availability by simple contact with an aqueous liquid medium. In addition, in Example 9, 182 g of paracetamol (drug belonging to class I of the Biopharmaceutical Classification System and having a solubility in water of 14 mg / ml), 728 g of microcrystalline cellulose Paracetamol microgranules obtained from a mixture of (AVICEL PH 101) and 90 g sodium carboxymethylcellulose are disclosed. EP-A-352,190, however, does not teach the use of cyclodextrin compounds as drug dissolution enhancers.

U.S. Pat.No. 5,362,860 discloses (by weight) 0.05% pyridine-based oxime (a drug that causes hydrolysis of aldehydes in an acidic environment), 70% cyclodextrin, 3% croscarmellose (crosslinked polymer) and 20.95 A composition having improved storage stability is disclosed comprising% microcrystalline cellulose (Table VI, Example C).

WO-A-99 / 12524 discloses (i) a first fraction capable of releasing at least 50% of the drug in the first 20 minutes by a constant dissolution method, and (ii) a second fraction for delayed and prolonged drug release. Providing an oral modified release multi-unit composition in unit dosage form comprising a drug formulation which allows to maintain the therapeutically active plasma concentration for a relatively long time while simultaneously initiating a therapeutic effect relatively rapidly or rapidly. Solve. The multi-unit of the first fraction can be granules provided that the surfactant can be added to the formulation, coated or uncoated pellets. The formulation of the first fraction depends on the particular drug, but typically includes wetting-granulation, and it has been found that antacid types or other alkalines have a significant enhancing effect on release rates.

U.S. Pat.No. 5,646,131 discloses insoluble or sparingly soluble drugs such as terpenadine (solubility in water of less than 0.01 mg / ml), surfactants (Twin 80 and sodium lauryl sulfate), cyclodextrins, Avicel PH 101 (microcrystalline cellulose ), And a rapid dissolving capsule containing a granule formulation comprising a disintegrant / swelling agent (Primojel (R), ie sodium carboxymethyl starch) having a weight ratio of 10:72 relative to Avicel ( Example 4). This capsule provides better drug absorption due to the presence of cyclodextrin, as evidenced by the figure showing 90% drug release within 45 minutes.

Avicel 581 (a combination of microcrystalline cellulose and sodium carboxymethyl cellulose) in Elbers et al. ( Drug Development and Industrial Pharmacy (1992) 18 (5): 501-517). Theophylline pellets having a drug loading of 10 to 50% obtained by extrusion-centrifugation are disclosed. Theophylline has a water solubility of 8 mg / ml (according to Merck Index, 12th edition (1996)) and high permeability [according to the FDA Guidance to Industry (2000)]. As a drug, it is therefore a drug belonging to class I of the biopharmaceutical classification system.

U.S. Pat. No. 4,235,892, known as florfenicol (flofenicol), is an antibacterial agent useful for veterinary purposes, including D- (threo) -1-p-methylsulfonyl phenyl-2-dichloroacetamido. A series of 1-aryl-2-acylamido-3-fluoro-1-propanols is disclosed, including -3-fluoro-1-propanol. Florfenicol is low in water solubility (about 1.3 mg / ml) as well as in many pharmaceutically acceptable organic solvents such as 1,2-propanediol, glycerin and benzyl alcohol. For oral administration, this 1-aryl-2-acylamido-3-fluoro-1-propanol can be combined in tablet form or even mixed with animal feed. Thus US Pat. No. 4,235,892 discloses the 1-aryl-2-acylamido-3-fluoro-1-propanol (drug loading: 8.3 wt% to 41.7 wt%), lactose, microcrystalline cellulose, starch and The preparation of tablets is initiated by pressing granules of a composition comprising magnesium stearate.

G. Amidon et al . Pharm. Res. (1995) 12: 413-420, the Biopharmaceutical Classification System (hereafter referred to as BCS) is classified into two classes of low solubility drugs, Class II and IV, and the classification of high solubility drugs. Provide class I. Application of the Biopharmaceutical Classification System to Veterinary Pharmaceutical Products in Advanced Drug Delivery Reviews (2002) 54: 805-824 by M. Martinz et al. According to Part I: Biopharmaceutics and Formulation Consideration, the drug substance is highly soluble when its highest dosage strength is soluble in up to 250 ml of an aqueous medium over a pH range of 1 to 7.5. Will be classified. In terms of its solubility in water (1.3 mg / ml) and the maximum dosage of 20 mg / kg (pig), the maximum dosage strength of fluorenicol administered to pigs is well below the limit for the definition of drug even when Class I BCS is employed. It is easy to determine the solubility in the excess amount of water. J. From The Veterinary Record (October 1999) by Voorspoels et al, florfenicol is classified as a class II compound that is not a highly soluble drug and does not exhibit absorption problems because it has good oral bioavailability. It is known that it can be.

There is a particular need in the prior art to provide a solid formulation of a drug having a solubility in water such as florfenicol or below. Florfenicol is a drug for oral administration to warm-blooded animals such as cattle, pigs, sheep, goats and poultry with naturally occurring bovine respiratory diseases, which are currently available only in the form of injectable solutions. To date, those skilled in the art have failed to devise such solid formulations of florfenicol which can be further mixed with animal feed as needed. There is also a need for solid formulations for drugs with low solubility for human therapy.

Summary of the Invention

The present invention relates to a drug classifiable or belonging to class II (low solubility and high permeability) or class IV (low solubility and low permeability) of the biopharmaceutical classification system, including drugs with very low solubility in water, (1) It is a non-aqueous solution comprising a dextrin-containing compound, or a combination of microcrystalline cellulose and a swellable polymer, or a pharmaceutically acceptable first excipient comprising said dextrin-containing compound and a mixture of said combination, and at least one solid fraction. The expectation that the compound is mixed with a pharmaceutically acceptable second excipient which is a wetting compound in an appropriate fraction and (2) it can be successfully formulated in an immediate release pharmaceutical dosage form under the conditions of formulating it into a granular composition, not a pellet composition. Based on findings Preferably, the granule formulation is advantageously obtained by a continuous production method comprising a low temperature extrusion step in the extrusion means. Based on the above teachings, the present invention also provides various pharmaceutical dosage forms, including the granule composition, such as fabrics and solid molded articles such as tablets and hard gelatin capsules. The invention also provides for the treatment of bacterial infections in humans and animals, such as bovine (e.g. bovine respiratory disease) and fish, by oral administration of an effective amount of the aforementioned rapid release pharmaceutical granular composition to a human or animal. It is about.

The present invention belongs to the field of drug delivery systems and immediate release. In particular, the present invention belongs to the field of rapid-release pharmaceutical granule compositions. More specifically, the present invention relates to the composition, wherein the drug loading for immediate release of the drug having low solubility in water is small to medium. The present invention also relates to various solid pharmaceutical dosage forms, such as sachets, gelatin capsules and tablets, comprising such immediate release granule compositions. Finally, the present invention relates to a method for the continuous preparation of the rapid release granule composition.

1 shows the release of hydrochlorothiazide from the granular composition according to the invention, expressed as a function of time.

2 shows the release of florfenicol from the granular composition according to the invention, expressed as a function of time.

3 shows a twin screw extruder useful for preparing the granule composition of the present invention.

In a first embodiment, the present invention

(i) one or more drugs classifiable to class II (low solubility and high permeability) or class IV (low solubility and low permeability) of the biopharmaceutical classification system, such as drugs with very low solubility in water as defined herein (Wherein the drug comprises from about 0.5% to about 20% by weight of the composition, preferably from 1 to 15% by weight), and (ii) a first selected from the group consisting of Excipients:

Swellable polymers: a combination of microcrystalline cellulose and swellable polymers, wherein the weight ratio of microcrystalline cellulose is greater than about 2: 100 and up to about 30: 100,

At least one dextrin-containing compound selected from the group consisting of maltodextrin, cyclodextrin and derivatives thereof, and

A mixture of said dextrin-containing compound and said combination; And

(iii) a non-aqueous wet compound or meltable compound, further comprising a wet amount of a second excipient comprising a solid fraction and optionally a liquid fraction.

In a second embodiment, the present invention

(a) a mixture comprising a solid fraction of drugs classifiable to class II or IV of the biopharmaceutical classification system, such as drugs with very low solubility in water, first excipient (ii), and second excipient (iii) Homogenizes,

(b) feeding the mixture obtained in step (a) and optionally the liquid fraction of the second excipient (iii) to an extrusion means having at least one mixing zone and at least one conveying zone, and

(c) extruding the material fed in step (b) while operating the extrusion means at a temperature below the melting point of the solid fraction of the second excipient until an immediate release pharmaceutical granule composition is obtained

It relates to a method for the continuous preparation of the rapid-release pharmaceutical composition comprising the steps of.

Hereinafter, a more detailed manner for carrying out the present invention will be described in more detail with regard to both immediate release pharmaceutical granule compositions and methods for their preparation. In a preferred embodiment, the first excipient (ii) can be a combination of microcrystalline cellulose and swellable polymers, said swellable polymers can be for example non-crosslinked carboxyalkylcelluloses such as sodium or calcium carboxymethylcellulose.

In another preferred embodiment of the invention, the first excipient (ii) may be present in the composition in an amount of about 40 to about 85 weight percent of the composition.

Microcrystalline cellulose, in particular its pharmaceutical grade, is known in the pharmaceutical industry for its high surface porosity and excellent capillary properties. It is available from a variety of commercial sources such as Avicel (R) PH 101 (commercially available from FMC Corporation, Philadelphia, Pa.), Emcocel (R) (Mendell), Vivocel ( R) (JRS Corporation) etc. are available. Microcrystalline cellulose is a partially purified depolymerized form of cellulose, which is obtained by treating the pulp derived from fibrous plant material with a mine. The acid is preferably exposed to and freed from crystalline sites that form cellulose crystalline aggregates by attacking the less refined or amorphous regions of the cellulose polymer chain. The reaction mixture is washed to remove the decomposed by-products and the obtained wet-cake does not contain water and the dried cellulose crystalline aggregates, or more usually microcrystalline cellulose, are recovered. Microcrystalline cellulose is a white, odorless, tasteless, relatively free-flowing powder that is insoluble in water, organic solvents, dilute alkalis, and dilute acids.

Swellable polymers suitable for use in the present invention are preferably easily miscible herein with microcrystalline cellulose, and in themselves colloidal particles in an aqueous environment form, for example, three-dimensional networks or lattice structures throughout the liquid phase. Can be defined as an ionic hydrocolloid polymer capable of forming a colloidal suspension. Preferred examples of such polymers include sodium carboxy such as those commercially available under the tradenames Nymcel (R), Tilose (R) and Blancose (R) (Aqualon). Pharmaceutical grades of methylcellulose are included. Preferably, the swellable polymer is a low molecular weight and / or low viscosity polymer. For example, when the swellable polymer is an uncrosslinked carboxyalkylcellulose metal salt, it should preferably have sufficient unsubstituted hydroxyl groups to hydrogen bond to the microcrystals of microcrystalline cellulose upon drying, and the substituents have water solubility imparting ability. Should have The degree of substitution of carboxyalkylcellulose should preferably be in the range of about 0.9 or less, more preferably in the range of 0.5 to 0.9. In addition, the viscosity of the 2% swellable polymer aqueous solution at 20 ° C. should preferably be less than 1,000 mPa · s, more preferably in the range of about 20 to 800 mPa · s.

The swellable polymer and microcrystalline cellulose may be provided separately when preparing the pharmaceutical granule composition of the present invention or may be present in the form of a co-processing formulation.

Simultaneous processing blends of microcrystalline cellulose and swellable polymers are known in the art in the form of pharmaceutically acceptable grades, such as Avicel (R) RC 581 and Avicel (R) CL 611 (both from FMC Corporation). Commercially available). This cellulosic blend alternatively contacts the two blending components in close proximity under suitable conditions, for example by applying a strong frictional force to a cleaned filter cake containing microcrystalline solids from acid decomposition of cellulose, resulting in cellulose crystallite aggregates. Can be made by further destroying and increasing the submicron particles. As the friction progresses, a sufficient amount of swellable polymer (such as sodium carboxymethyl cellulose) is added to the aqueous mixture to at least partially coat the individual microcrystals of microcrystalline cellulose. Upon friction completion, the blend is dried and recovered. The dried product is redispersible directly in the aqueous medium, so that a gel is obtained. It is important for the efficacy of the product in the present invention that the formulation is a non-disintegrating insoluble water dispersible powder prior to granulation by mixing with the low solubility drug and the second excipient. Preferably at least about 1 wt%, more preferably at least about 30 wt% of the powder blend particles have an average size of about 1.0 μm or less, as determined by electron microscopic irradiation.

For optimum efficiency, the weight ratio of said swellable polymer to microcrystalline cellulose in the immediate release pharmaceutical granule composition of the present invention in the (simultaneous processing) formulation as defined above, respectively, is from about 2: 100 to about 30: Or less, preferably about 7: 100 to 20: 100.

Drug dissolution enhancers such as maltodextrins, cyclodextrins and derivatives thereof, especially their pharmaceutically acceptable grades, are known in the art and are available from various commercial sources. It may be referred to as a starch cyclic degradation product having 6 to 8 glucose residues or alternatively as a cyclic oligosaccharide consisting of L-glucose molecules linked by α or β acid bonds having a toric form. One suitable representative embodiment of the cyclodextrin derivative enhancer consists of hydroxypropyl-β-cyclodextrin.

Preferably the amount of first excipient represents about 40% to about 80% by weight of the immediate release pharmaceutical granule composition, depending on the amount of other excipients (eg, fillers) optionally present therein.

According to the invention, the immediate release preferably releases at least about 50% of the drug within 30 minutes in water, preferably at least about 70% of the drug within 10 minutes in water, under physiological temperature and pH conditions, more Preferably at least about 80% release of the drug in water within 10 minutes. As shown in the Examples below, the present invention is also a drug having a low but not very low solubility in water, comprising a drug having a relatively high dosage (ie, from about 10% to about 20% of the composition) for therapeutic efficiency For example, florfenicol.

The immediate release pharmaceutical granule composition of the present invention may further comprise one or more pharmaceutically acceptable fillers. The pharmaceutically acceptable fillers can be selected from, for example, hydrocolloids (eg, xanthan gum), binders, glidants, lubricants, surfactants and diluents. The term "pharmaceutically acceptable filler" as used herein means that it does not have any therapeutic and / or prophylactic effect at all, but does not negatively affect the therapeutic or prophylactic properties of the drug or pharmaceutically active ingredient formulated. It is intended to refer to any substance that is inert at. The nature and amount of such fillers is not critical to the present invention. They include, for example, binders such as starch, gelatin, glucose, alginic acid, sodium and calcium alginate, water soluble acrylic (co) polymers, polyvinylpyrrolidone, polyamino acids, ethylene-vinyl acetate copolymers and the like; Natural and synthetic inorganic fillers or glidants such as fumed (colloidal) silicas (such as those commercially available under the tradename Aerosil (R)), magnesium silicates such as talc, diatomaceous earth, aluminum silicates such as kaolinite, mont Morillonite or meteorite, magnesium aluminum silicates such as attapulgite and vermiculite, carbon such as charcoal, sulfur and highly disperse silicic acid polymers; Water soluble diluents such as lactose, sorbitol and the like. According to the invention, drug (i) is classifiable as class II or IV of BCS, preferably at room temperature and physiological pH, less than about 2.5 mg / ml, even 0.1 to 1 mg / ml (ie US Pharmacopoeia) Have a solubility in water of "very slightly soluble", as defined in, even less than 0.1 mg / ml (ie, "actually insoluble" as defined in the US Pharmacopoeia), even less than about 5 μg / ml Even in water, as low as about 0.2 μg / ml. Non-limiting examples of such drugs include, for example, chlorothiazide, hydrochlorothiazide, nimodipine, flufenamic acid, furosemide, mefenamic acid, bendroflumethiazide, benzthiazid, ethacrynic acid, niece Trendy Fin, Itraconazole, Saperconazole, Troglitazone, Prazosin, Atobaceon, Danazol, Glibenclamide, Griseofulvin, Ketoconazole, Carbamazepine, Sulfazin, Florfenicol, Acetohexamide, Aza Marlin, benzbromarone, benzyl benzoate, betamethasone, chloramphenicol, chlorpropamide, chlorthalidone, clofibrate, diazepam, dicoumarol, digitoxin, etotoin, glutetimide, hydrocortisone, Hydroflumetiazide, hydroquinine, indomethacin, ibuprofen, ketoprofen, naproxen, kelin, nitrazepam, nitrofurantoin, novalgin, oxazapham, papaverine, phenylbutazone, phenytoin, fructose Rednisolone, prednisone, reserpin, spironolactone, sulfabenzamide, sulfadimethoxin, sulfamerazine, sulfamethazine, sulfamethoxypyridazine, succinyl sulfatiazole, sulfamethazole, sulfamethoxazole ( And also mixtures with trimethoprim), sulfapefenazole, sulfatiazole, sulfisoxazole, sulfide, testosterone and diaminopyrimidine. Suitable examples of diaminopyrimidines include, but are not limited to, 2,4-diamino-5- (3,4,5-trimethoxybenzyl) pyrimidine (known as trimethoprim), 2,4-diamino -5- (3,4-dimethoxybenzyl) pyrimidine (also known as diaberrydine), 2,4-diamino-5- (3,4,6-trimethoxybenzyl) pyrimidine, 2,4 -Diamino-5- (2-methyl-4,5-dimethoxybenzyl) pyrimidine (known as ormethoprim), 2,4-diamino-5- (3,4-dimethoxy-5-bro Mobenzyl) pyrimidine and 2,4-diamino-5- (4-chlorophenyl) -6-ethylpyrimidine (known as pyrimethamine). The above-mentioned drugs are described in G. Amidodon et al . Pharm. Res. (1995) 12: 413-420, which are known to belong to class II (low solubility and high permeability) or class IV (low solubility and low permeability) of the biopharmaceutical classification system. As will be appreciated by those skilled in the art, the drug belongs to various therapeutic classes including diuretics, antihypertensives, antiviral agents, antibacterial agents, antifungal agents and the like, and is not limited to human or animal use only.

According to the invention, the granules of the immediate release pharmaceutical granule composition preferably have a diameter in the range of about 100 to 2,500 μm.

The second excipient (iii) of the rapid-release pharmaceutical granule composition is polyethylene glycol and polypropylene glycol having a weight average molecular weight of about 300 to about 5,000; Glycerol; Propylene glycol and glycerides (e.g., mono-, di- and triglycerides of polyethyleneglycol fatty acid esters, including those commercially available under the tradename Gelucire (R)). Suitable examples of the latter include those having both a moiety derived from glycerides and a moiety derived from polyethylene glycol esters. For example, it is suitable to use polyglycosylated glycerides. As used herein, the term "polyglycosylated glyceride" means that the hydrophilic-lipophilic balance (HLB) is controlled by the chain length of polyethylene glycol (PEG), the melting point of which is the fatty acid, chain length of PEG, and saturation of fatty chains. PEG mono- and diesters and mono- of C ₈ -C ₁₈ fatty acids, thus controlled by the starting oil and optionally comprising glycerol and / or free PEG, preferably having a molecular weight of about 200 to about 600 A mixture of di- and triglycerides. Likewise, the expression “C ₈ -C ₁₈ fatty acids” as used herein refers to saturated acids of caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid, and their A mixture of unsaturated acids corresponding to As will be appreciated by those skilled in the art, the fraction of fatty acids may vary depending on the functional relationship with the starting oil. Examples of the latter include, but are not limited to, saturated polyglycolated C ₈ -C ₁₀ glycerides such as PEG-8 caprylic acid / ca sold under the trade name Labrasol by Gattefosse Corporation. Phthalic acid glyceride esters; PEG-6 caprylic / capric glycerides sold under the tradename Softigen 767 by Huls Aktiengesellschaft; PEG-60 corn glycerides sold under the trade name Crovol M-70 by Croda; Ceteareth-20 sold under the tradename Emulgin B2 by Henkel Corporation; Diethylene glycol monoethyl-ether sold under the name Transcutol by Gatefoss Corporation; Having a melting point in the range of about 42 to 48 ° C. and an HLB in the range of about 8 to 16, such as those sold under the trademarks GELUSURE 48/09, GELUSURE 44/14 and GELUSURE 42/12 by GATEPOSE CORPORATION. A mixture of C ₈ -C ₁₈ saturated polyglycosylated glycerides; And mixtures of the foregoing with various fractions. When using polyethylene glycol, for example, it may comprise a high molecular weight solid fraction and a low molecular weight liquid fraction that acts as a plasticizer.

In one preferred embodiment of the invention, the second excipient (iii) may be present in the immediate release granule composition in an amount of about 15 to about 40% by weight of the composition. In another preferred embodiment of the invention, the weight ratio of the liquid fraction: solid fraction of the second excipient (iii) may be from 0: 1 (without liquid fraction) to about 1: 2, more preferably 1: 3 or less. . In another preferred embodiment of the invention, for example, when maltodextrin is used as the first excipient (ii) and polyethylene glycol is used as the second excipient (iii), the first excipient (ii): second excipient ( The weight ratio of iii) is in the range of about 1: 1 to about 5: 1.

According to the invention, the rapid-release pharmaceutical granules composition may further comprise one or more other drugs which differ from drugs of low solubility in water, provided that, in particular, when a combination drug therapy is desired, the drugs belonging to the same therapeutic class preferably. Can be.

The method of the present invention preferably comprises a barrel having a granulation chamber equipped with an inlet for feeding a solid fraction of drug (i), a first excipient (ii) and a second excipient (iii), and at least one continuous operation. It is carried out in an apparatus such as a twin screw extruder, comprising a rotational conveying means. The extruder preferably operates at temperatures below about 45 ° C., more preferably below about 35 ° C., ie there is no need to provide a heating zone on the extruder, which is a complex means for controlling and monitoring the temperature of the extruder. There is no need to provide it. The extruder is operated at a rotational speed of preferably about 5 to 300 rpm, depending on the desired low, medium or high shear force. The continuously operated rotary conveying means of the extruder comprises at least one mixing zone and at least one conveying zone. The arrangement and number of such zones can vary widely, but one or more mixing zones are most preferred and it is very advantageous to induce interactions between the various components of the composition to be extruded. Thus, the remainder of the screw can be configured as a transfer zone. Single or double lead release screws can be used. As a standard in the art, the ratio of length to diameter of each rotary transport means can be in the range of about 15 to about 60.

The invention also provides a solid molded article comprising a core composed of a rapid release pharmaceutical granule composition as defined above. This solid molded article may be in the form of a tablet or hard gelatin capsule. From the overgrape compositions, methods of making tablets (eg, compression), or methods of making hard gelatin capsules are known to those skilled in the art. In the case of tablets, according to standard practice in the art, solid shaped articles may further comprise a coating.

As used herein, the term “solid molded article” refers to any article that is in the hard solid state at temperatures below about 60 ° C. and has a clear geometric shape, such as general tablets, effervescent tablets, pills, lozenges (lozenge tablets). ) And other compressed dosage forms.

Solid molded articles of the invention include additives commonly used in the formulation of such articles, such as flavoring agents (eg, anetol, benzaldehyde, vanillin, ethyl vanillin, ethyl acetate, methyl salicylate, etc.), lubricants (eg, Magnesium stearate), sweeteners (such as sucrose, mannitol, aspartame, saccharin and salts thereof), colorants and / or buffers, optionally further.

The present invention also provides a fabric comprising an immediate release pharmaceutical granule composition as defined above.

The present invention provides an advantage over existing formulations of low solubility drugs. In particular, the present invention optionally provides a solid formulation of florfenicol for oral administration to warm-blooded animals such as cattle, pigs, sheep, goats and poultry with naturally occurring bovine respiratory disease, optionally with animal feed. The present invention also provides solid formulations of trimethoprim (usually trimetoprim / sulfadiazine), optionally in combination with sulfadiazine, for oral administration to fish as an effective antibacterial agent against gram-positive and gram-negative bacteria. Weight ratio of about 1: 5).

The following examples are provided merely to illustrate various embodiments of the invention and are not intended to limit the scope of the invention.

Example 1-Twin Screw Extruder for Preparing Pharmaceutical Granule Composition

The twin screw extruder used to perform the following pharmaceutical granule preparation is described in FIG. 3. It consists of seven distinct bands, where bands (1), (2), (4) and (6) are three transport bands, and bands (3) and (5) are two mixed bands, Zone 7 is a densification band (which may alternatively be omitted if desired). The extruder is located in a granulation chamber equipped with an inlet for supplying drugs and various excipients.

Examples 2 and 3-Pharmaceutical Granule Formulations Containing Maltodextrin and Xanthan Gum

The following formulation was prepared using the extrusion equipment of Example 1:

Low Water Soluble Drugs: 100 g

Polyethylene glycol 400: 52.5 g

Polyethylene glycol 4000: 187.5 g

Maltodextrin 01982: 622.5 g

Xanthan Gum: 37.5 g

Maltodextrin 01982 is a neutral taste medium-DE maltodextrin with good dispersibility, which is commercially available from Cerestar Co., Ltd., Neu-sur-Seine, France. The solid fraction of the formulation consisting of hydrochlorothiazide (Example 2), PEG 4000, maltodextrin and xanthan gum was homogenized in a planetary mixer. This mixture was fed to a twin screw extruder at a rate of 29.9 g / min. The liquid phase (PEG400) was pumped continuously to the twin screw extruder at a rate of 6.9 g / min. The screw speed during the extrusion was 250 rpm. By setting the temperature of the different zones of the twin screw extruder to 25 ° C., 25 ° C. in zone (1), 26 ° C. in zone (2), 26 ° C. in zone (3) and 25 ° C. in zones (4) and (5) The experimental extrusion temperature of was calculated.

In the case of florfenicol (Example 3) used as a drug instead of hydrochlorothiazide, the same parameters were used and the experimental temperatures measured in zones (1) to (5) were 26 ° C., 28 ° C., 28 ° C., respectively. 27 ° C. and 25 ° C.

Extruded granules were collected, sieved and analyzed for drug solubility (data shown in FIGS. 1 and 2 (Formulations B and D)). 1 shows that after 10 minutes 72% release of hydrochlorothiazide (Example 2) is obtained. 2 shows that after 10 minutes an 80% release of florfenicol (Example 3) has already been obtained, and after 20 minutes a 100% release is obtained.

Examples 4 and 5-Pharmaceutical Granule Formulations Comprising Microcrystalline Cellulose

The following formulation was prepared using the extrusion equipment of Example 1:

Low Water Soluble Drugs: 100 g

Polyethylene glycol 400: 52.5 g

Polyethylene glycol 4000: 250 g

Avicel PH 101: 298.75 g

Avicel CL611: 298.75 g

The solid fraction of the formulation consisting of hydrochlorothiazide (Example 4), PEG 4000, Avicel PH 101 / Avicel CL 611 [commercially available from FMC Corporation, Philadelphia, Pa.] Was homogenized in a planetary mixer. . This mixture was fed to a twin screw extruder at a rate of 27.6 g / min. The liquid phase (PEG 400) was pumped continuously to the twin screw extruder at a rate of 9.2 g / min. The screw speed during the extrusion was 250 rpm. The temperatures of the different zones of the twin screw extruder were set to 25 ° C., yielding experimental extrusion temperatures of 25 ° C., 28 ° C., 27 ° C., 26 ° C., and 25 ° C., respectively, in zones (1) to (5).

In the case of florfenicol (Example 5) used as a drug instead of hydrochlorothiazide, the same parameters were used and the experimental temperatures measured in zones (1) to (5) were 25 ° C., 26 ° C., 27 ° C., respectively. 27 ° C. and 28 ° C.

Extruded granules were collected, sieved and analyzed for drug solubility [data shown in FIGS. 1 and 2 (Formulations A and C)]. Figure 1 shows that after 10 minutes a 100% release of hydrochlorothiazide (Example 4) is obtained. 2 shows that after 10 minutes a 78% release of florfenicol (Example 5) has already been obtained and after 15 minutes a 100% release is obtained.

Claims (22)

(i) at least one drug classifiable to class II or IV of the Biopharmaceutical Classification System, wherein the drug constitutes at least about 0.5% to about 20% by weight of the composition. ), (ii) a first excipient selected from the group consisting of: Swellable polymers: a combination of microcrystalline cellulose and swellable polymers, wherein the weight ratio of microcrystalline cellulose is greater than about 2: 100 and up to about 30: 100, At least one dextrin-containing compound selected from the group consisting of maltodextrin, cyclodextrin and derivatives thereof, and A mixture of said dextrin-containing compound and said combination, and (iii) An immediate release pharmaceutical granule composition, which is a non-aqueous wet compound or meltable compound, further comprising a wet amount of a second excipient comprising a solid fraction and optionally a liquid fraction. (a) homogenizing a mixture comprising a solid fraction of said drug (i), a first excipient (ii), and a second excipient (iii) classifiable to class II or IV of the biopharmaceutical classification system, (b) feeding the mixture obtained in step (a) and optionally the liquid fraction of the second excipient (iii) to an extrusion means having at least one mixing zone and at least one conveying zone, and (c) extruding the material fed in step (b) while operating the extrusion means at a temperature below the melting point of the solid fraction of the second excipient until an immediate release pharmaceutical granule composition is obtained A process for the continuous preparation of a rapid-release pharmaceutical composition according to claim 1 comprising the steps of: The drug (i) is chlorothiazide, hydrochlorothiazide, nimodipine, flufenamic acid, furosemide, mefenamic acid, bendroflumetiazide, benzthiazide, ethacrynic acid, nitridipine, itraconazole, Troglitazone, Atobacuo, Danazol, Glibenclamide, Griseofulvin, Ketoconazole, Carbamazepine, Florfenicol, Sulfaazine, Acetohexamide, Azamalin, Benzbromarone, Benzyl Benzoate, Betamethasone, Chlor Amphenicol, chlorpropamide, chlortalidone, clofibrate, diazepam, dicoumarol, digitoxin, etotoin, glutetimide, hydrocortisone, hydroflumethiazide, hydroquinine, indomethacin, Ibuprofen, ketoprofen, naproxen, kelin, nitrazepam, nitrofurantoin, novalgin, oxazepamine, papaverine, phenylbutazone, phenytoin, prednisolone, prednisone, reserpine, spironolactone, Sulfabenzamide, sulfadimethoxin, sulfamerazine, sulfamethazine, sulfamethoxypyridazine, succinyl sulfatiazole, sulfamethazole, sulfamethazole, sulfaphenazole, sulfatiazole, sulfi soxazole, sulfide The rapid release pharmaceutical granule composition according to claim 1, or the method according to claim 2, selected from the group consisting of testosterone and diaminopyrimidine. The immediate release pharmaceutical granule composition according to claim 1, wherein the first excipient (ii) is a combination of microcrystalline cellulose and a swellable polymer, and the swellable polymer is uncrosslinked sodium or calcium carboxymethyl-cellulose. According to the method. The immediate release pharmaceutical granule composition according to claim 1, wherein the immediate release is release of at least about 50% of the drug in water within 30 minutes. The immediate release pharmaceutical granule composition according to claim 1, wherein the immediate release is release of at least about 70% of the drug in water within 10 minutes. The immediate release pharmaceutical granule composition of claim 1, further comprising one or more pharmaceutically acceptable fillers. 8. The immediate release pharmaceutical granule composition of claim 7, wherein the pharmaceutically acceptable filler is selected from hydrocolloids, binders, glidants, lubricants, surfactants and diluents. The immediate release pharmaceutical granule composition according to claim 1, or the method according to claim 2, wherein the drug (i) has a solubility in water of less than about 2.5 mg / ml. . The rapid release pharmaceutical granule composition according to claim 1, or the method according to claim 2, wherein the drug (i) has a solubility in water of less than about 5 μg / ml. . The immediate release according to any one of claims 1 or 3, wherein the first excipient (ii) is a combination of microcrystalline cellulose and a swellable polymer and the swellable polymer is a non-crosslinked carboxyalkylcellulose metal salt. Pharmaceutical granule composition, or method according to claim 2. The rapid release pharmaceutical granule composition according to claim 1, or the method according to claim 2, wherein the granules have a diameter in the range of about 100 to 2,500 μm. Polyethylene glycol and polypropylene glycol, wherein the second excipient (iii) has a weight average molecular weight of about 300 to about 5,000; Glycerol; The rapid-release pharmaceutical granule composition according to claim 1, or the method according to claim 2, selected from the group consisting of propylene glycol and glycerides. 14. The immediate release pharmaceutical granule composition according to any one of claims 1 or 3 to 13, further comprising at least one other drug which is different from the classifiable drug of class II or IV of the biopharmaceutical classification system. The method of claim 2 wherein said extrusion means is a twin screw extruder. The method of claim 2 or 15, wherein the extrusion means is operated at a temperature of about 45 ° C. or less. The method of claim 2, wherein the extrusion means is operated at a rotational speed of about 5 to 300 rpm. A solid molded article comprising a core composed of the rapid-release pharmaceutical granule composition according to claim 1 or claim 3. 19. The solid molded article according to claim 18 in the form of a tablet or hard gelatin capsule. 20. The solid molded article according to claim 18 or 19, which is in the form of a tablet further comprising a coating. A sachet comprising an immediate-release pharmaceutical granule composition according to claim 1, or claim 3. The rapid release pharmaceutical granule composition according to claim 1, or the solid molded article according to claim 18, in combination with an animal feed for oral administration to an animal.